The Oregon Brain Aging Study (OBAS) is a longitudinal study of factors related to healthy brain aging in the oldest old (those e age 85), the fastest growing segment of the population and those at highest risk for dementia. During the past 20 years the OBAS has examined the trajectory and meaning of aging change across a range of markers such as brain volumes, clinical profiles, genetics and brain pathology, identifying a latent period of a decade or more when individuals appear to have presymptomatic disease prior to developing frank dementia. Among factors leading to cognitive decline in this latent period, those related to vascular disease stand out. A prominent marker of this vascular disease associated with aging is commonly seen on magnetic resonance imaging (MRI) of the brain and appears as white matter hyperintensities (WMHs). These WMHs have important implications for brain function since the white matter contains critical pathways for coordinated brain function. Disruption of these pathways is associated with significant cognitive and motor impairments. Understanding the mechanisms that lead to WMHs and related disruption of the white matter is fundamental to ultimately treating or preventing cognitive and functional decline associated with cerebrovascular disease. Accordingly, in this application we propose to examine in the oldest old, underlying mechanisms leading to this highly prevalent white matter change by assessing cerebral blood flow (CBF) and related microstructural white matter disruption in the brain using new high field MRI techniques. To achieve this goal we will pursue three tightly related research aims. First, we propose to determine the role of changes in CBF measured with non-invasive arterial spin labeling (ASL) MRI on the development of WMHs to determine if altered CBF is present in normal appearing white matter in elderly with WMHs already present in their brain, and if over time, altered CBF precedes the formation of pathologic white matter change. Second, we plan to characterize the extent of white matter disruption related to cerebrovascular disease markers such as low CBF and high volumes of WMH by examining the extent of microstructural white matter disruption seen with diffusion tensor imaging (DTI) MRI. Finally, we plan to Identify MRI markers (CBF, WMH volume, brain integrity) that best predict rates of clinical (cognitive and motor) decline and the post mortem brain pathologies that are most closely tied to these changes during life. The project will be conducted with over 100 OBAS oldest old volunteers who will have annual standardized clinical and MRI assessments. MRI will entail the use of both 3 Tesla and a special 7 Tesla MRI instrument to provide high-resolution images of CBF (ASL) and microstructural (DTI) damage over time. Given the nature of the cohort a significant number have and will donate their brain for study allowing for post mortem identification of MRI and other clinical changes observed during life that best index the neuropathologies found on autopsy. As part of this effort, unique data contributed by over 100 OBAS participants who had annual MRI scans and died during the prior 20 years will be used to examine WMH volume accumulation during their lives and how this change relates to the major age-associated pathologies (vascular as well as Alzheimer's disease lesions) seen at post mortem examination of their brain. PUBLIC HEALTH RELEVANCE: Decline in cognitive and mobility functions are the major causes of loss of independence with aging. This is especially of concern for the 3 million veterans currently age 85 or older as up to half will develop cognitive decline. Much of this decline is related to extremely common age-related vascular disease in the brain. These vascular changes are of particular interest in that existing strategies could be readily applied toward remediation or prevention of vascular related cognitive and mobility impairment today if we understood where and when they first occur and the underlying inciting factors leading to their emergence in the brain. Thus, this brain research that will ultimately guide how to best treat or prevent this major cause of loss of independence is of highest priority for veterans and all Americans facing the challenges of aging.